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Heart failure with preserved ejection fraction: Squaring the circle between comorbidities and cardiovascular abnormalities

  • Author Footnotes
    1 These authors equally contributed to the work
    Alberto Maria Marra
    Footnotes
    1 These authors equally contributed to the work
    Affiliations
    Department of Translational Medical Sciences, University of Naples “Federico II”, Napoli, Italy

    Interdisciplinary Research Centre on Biomaterials (CRIB), Federico II University, Naples, Italy

    Center for Pulmonary Hypertension, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
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  • Author Footnotes
    1 These authors equally contributed to the work
    Leonardo Bencivenga
    Footnotes
    1 These authors equally contributed to the work
    Affiliations
    Gérontopôle de Toulouse, Institut du Vieillissement, CHU de Toulouse, France

    Department of Advanced Biomedical Sciences, University of Naples “Federico II”, Napoli, Italy
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  • Roberta D'Assante
    Affiliations
    Department of Translational Medical Sciences, University of Naples “Federico II”, Napoli, Italy
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  • Giuseppe Rengo
    Affiliations
    Department of Translational Medical Sciences, University of Naples “Federico II”, Napoli, Italy

    Istituti Clinici Scientifici Maugeri SpA Società Benefit, Telese, Italy
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  • Antonio Cittadini
    Correspondence
    Corresponding author at: Department of Translational Medical Sciences, University of Naples "Federico II" 80131 Naples, Italy
    Affiliations
    Department of Translational Medical Sciences, University of Naples “Federico II”, Napoli, Italy

    Interdisciplinary Research Centre on Biomaterials (CRIB), Federico II University, Naples, Italy
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  • Author Footnotes
    1 These authors equally contributed to the work
Published:January 12, 2022DOI:https://doi.org/10.1016/j.ejim.2022.01.019

      Highlights

      • According to forecasts two third of all heart failure patients will belong to heart failure with preserved ejection fraction (HFpEF) by year 2050, overwhelming those affected by heart failure with reduced ejection fraction (HFrEF).
      • Both epidemiological and mechanistic studies support the concept that HFpEF represents true HF although aggravated by a collection of comorbidities.
      • There is urgent need of improving its phenotyping due to the high degree of disease heterogeneity within HFpEF that lead to the failure of randomized clinical trials in demonstrating a remarkable impact of drugs in improving its morbidity and mortality.

      Abstract

      Heart Failure with preserved Ejection Fraction (HFpEF) is nowadays considered a major healthcare issue. According to forecasts two third of all Heart Failure patients will belong to this phenotype by year 2050, overwhelming those affected by Heart Failure with reduced Ejection Fraction (HFrEF). Both epidemiological and mechanistic studies support the concept that HFpEF represents true HF although aggravated by a collection of comorbidities. There is urgent need of improving its phenotyping due to the high degree of disease heterogeneity within HFpEF that lead to the failure of randomized clinical trials in demonstrating a remarkable impact of drugs in improving its morbidity and mortality.

      Graphical abstract

      Keywords

      1. Introduction

      The original descriptions of Heart Failure (HF) with preserved ejection fraction (HFpEF) dates back to the mid-1980s, and, for approximatively a decade, studies on this HF subtype consisted of comparative reports or case series with great heterogeneity in terms of prevalence and clinical implications [
      • Vasan R.S.
      • Benjamin E.J.
      • Levy D.
      Prevalence, clinical features and prognosis of diastolic heart failure: An epidemiologic perspective.
      ]. Accordingly, the most recent guidelines provided by European Society of Cardiology for the management of acute and chronic HF indicate that 50% of patients have Heart Failure with reduced Ejection Fraction (HFrEF) and the other half suffers from HFpEF/HFwith mildy reduced Ejection Fraction  [
      • McDonagh T.A.
      • Metra M.
      • Adamo M.
      • Gardner R.S.
      • Baumbach A.
      • Böhm M.
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ]. Mounting evidence coming from mechanistic studies shifted the focus from a mere development of severe diastolic dysfunction to a complex syndrome in which comorbidities activate several loco-regional and molecular systemic pathways. The common hallmark is a low grade inflammatory status, resulting in a clinical syndrome symptomatically difficult to distinguish from the companion HFrEF [
      • Paulus W.J.
      • Tschöpe C.
      A novel paradigm for heart failure with preserved ejection fraction: Comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.
      ]. In the complex scenario linking comorbidities and HFpEF, many gray areas still remain. First, whether HFpEF represents a true HF or just a collection of comorbidities. Moreover, it has still to be clarified whether distinct cardiovascular (CV) abnormalities are detectable in HFpEF and if this syndrome can be divided in different phenotypes according to a specific clustering of distinct comorbidities. The present review aims to elucidate the aforementioned outstanding issues by i) reporting epidemiological data on HFpEF and comorbidities, ii) addressing the pathophysiological underpinnings of the relationship between comorbidities and HFpEF provided by translational studies, iii) exploring the possibility of clustering HFpEF onto different phenotypes according to specific comorbidities profile. Finally, we will try to tackle the possibility of treating the underlying comorbidities individually, as a promising approach in the therapy of this syndrome. This latter point is of particular interest, given the recently published breakthrough data of the The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) [
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Ferreira J.P.
      • Bocchi E.
      • Böhm M.
      • et al.
      Empagliflozin in Heart Failure with a Preserved Ejection Fraction.
      ] that for the first time reported a positive effect on hard outcomes in HFpEF, exerted by the antidiabetic drug empagliflozin.

      1.1 Are we facing an HFpEF tsunami in the next decades? An epidemiological outlook

      HF represents a major health burden worldwide, affecting 1–2% of the population in developed countries. Its prevalence shows a continuous increase, and is expected to reach 3% of U.S. population by 2030 [
      • Savarese G.
      • Lund L.H.
      Global Public Health Burden of Heart Failure.
      ]. The reasons behind this trend can be found in the demographic growth of the global population, the increasing proportion of elderly subjects, and the improved diagnostic and therapeutic approaches which also enhance patients’ survival [
      • Groenewegen A.
      • Rutten F.H.
      • Mosterd A.
      • Hoes A.W.
      Epidemiology of heart failure.
      ].
      It is worth mentioning that aging is considered the main factor responsible for the overall increase in HF incidence in the developed countries, as age-adjusted HF incidence may even decrease, due to the improved management of cardiovascular disease (CVD) [
      • McDonagh T.A.
      • Metra M.
      • Adamo M.
      • Gardner R.S.
      • Baumbach A.
      • Böhm M.
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ]. Accordingly, HF is particularly widespread in the elderly, and is considered one of the main geriatric syndromes, being the most frequent cause of hospitalization in patients aged 65 years and over [
      • Dharmarajan K.
      • Rich M.W.
      Epidemiology, Pathophysiology, and Prognosis of Heart Failure in Older Adults.
      ].
      In epidemiological studies, HF assessment is complex because it is based on various diagnostic criteria and often derived from hospital diagnostic codes which can be influenced by administrative and other non-clinical factors. Indeed, HF classification according to left ventricle ejection fraction (LVEF) is relatively recent and only a few years ago homogeneity in the diagnostic assessment was achieved [
      • Pfeffer M.A.
      • Shah A.M.
      • Borlaug B.A.
      Heart Failure with Preserved Ejection Fraction in Perspective.
      ]. From several registries and population-based studies, including the Framingham Heart Study, the Strong Heart Study and the Cardiovascular Health Study, it emerges that HFpEF constitutes a large proportion (>50%) of the overall HF cases  [
      • Pfeffer M.A.
      • Shah A.M.
      • Borlaug B.A.
      Heart Failure with Preserved Ejection Fraction in Perspective.
      ]. Accordingly, the most recent guidelines provided by European Society of Cardiology (ESC) for the management of acute and chronic HF indicate that 50% of patients have HFrEF and the other half suffers from HFpEF/HFmrEF [
      • McDonagh T.A.
      • Metra M.
      • Adamo M.
      • Gardner R.S.
      • Baumbach A.
      • Böhm M.
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ].
      HFpEF is a complex clinical syndrome resulting from the interplay among several risk factors which in turn determine heart dysfunction. The prevalence of risk factors contributing to HFpEF development may vary between affected individuals, and they synergistically concur to increase the risk of HF onset and progression [
      • Maurer M.S.
      • King D.L.
      • El-Khoury Rumbarger L.
      • Packer M.
      • Burkhoff D.
      Left heart failure with a normal ejection fraction: Identification of different pathophysiologic mechanisms.
      ]. Although evidences on ethnic and racial differences are still limited, gender-based differences have been reported with black women suffering from higher HFpEF rates compared to other race- and sex-groups [
      • Chang P.P.
      • Wruck L.M.
      • Shahar E.
      • Rossi J.S.
      • Loehr L.R.
      • Russell S.D.
      • et al.
      Trends in hospitalizations and survival of acute decompensated heart failure in four US communities (2005–2014) ARIC study community surveillance.
      ]. In almost all studies it has been shown that advanced age and female sex are more frequent in HFpEF than in HFrEF [
      • Groenewegen A.
      • Rutten F.H.
      • Mosterd A.
      • Hoes A.W.
      Epidemiology of heart failure.
      ]. High prevalence of cardiovascular comorbidities and risk factors in HFpEF has been widely described, with arterial hypertension being the most prevalent condition in HFpEF patients [
      • Andersson C.
      • Vasan R.S.
      Epidemiology of Heart Failure with Preserved Ejection Fraction.
      ]. Coronary artery disease (CAD), although more prevalent in HFrEF, is a common condition also in HFpEF, accounting for a percentage of patients ranging from 35 to 60% in epidemiological studies [
      • Lam C.S.P.
      • Donal E.
      • Kraigher-Krainer E.
      • Vasan R.S
      Epidemiology and clinical course of heart failure with preserved ejection fraction.
      ], and it is associated with increased risk of LVEF decline and higher mortality [
      • Hwang S.J.
      • Melenovsky V.
      • Borlaug B.A.
      Implications of coronary artery disease in heart failure with preserved ejection fraction.
      ]. Furthermore, the burden of comorbidities in HFpEF also includes obesity, atrial fibrillation, diabetes mellitus, chronic kidney disease [
      • Lam C.S.P.
      • Donal E.
      • Kraigher-Krainer E.
      • Vasan R.S
      Epidemiology and clinical course of heart failure with preserved ejection fraction.
      ]. Of note, all the aforementioned conditions are highly prevalent in late life [
      • Bencivenga L.
      • Grieco F.V.
      • Femminella G.D.
      • de Lucia C.
      • Komici K.
      • Rengo C.
      • et al.
      Management and Treatment of Cardiovascular Diseases in the Elderly.
      ] and the growing percentage of elderly in the global population will be responsible for the predicted further increase in HFpEF incidence and prevalence in the next future.
      Although no doubt remains on the pathophysiological correlation between HFpEF and these comorbidities, with a great impact on prognosis, it remains to be completely elucidated whether the burden of comorbidities is quantitatively higher than in HFrEF [
      • Pfeffer M.A.
      • Shah A.M.
      • Borlaug B.A.
      Heart Failure with Preserved Ejection Fraction in Perspective.
      ]. In this context, it has been described that specific conditions are more common in each HF subgroup (e.g. obesity is associated with higher incidence of HFpEF [
      • Savji N.
      • Meijers W.C.
      • Bartz T.M.
      • Bhambhani V.
      • Cushman M.
      • Nayor M.
      • et al.
      The Association of Obesity and Cardiometabolic Traits With Incident HFpEF and HFrEF.
      ]) and that the mean number of comorbidities is higher in HFpEF patients than HFrEF ones [
      • Ather S.
      • Chan W.
      • Bozkurt B.
      • Aguilar D.
      • Ramasubbu K.
      • Zachariah A.A.
      • et al.
      Impact of Noncardiac Comorbidities on Morbidity and Mortality in a Predominantly Male Population With Heart Failure and Preserved Versus Reduced Ejection Fraction.
      ].
      Real world and most observational studies consistently describe similar survival in patients with HFpEF compared to HFrEF [
      • Tsao C.W.
      • Lyass A.
      • Enserro D.
      • Larson M.G.
      • Ho J.E.
      • Kizer J.R.
      • et al.
      Temporal Trends in the Incidence of and Mortality Associated With Heart Failure With Preserved and Reduced Ejection Fraction.
      ], nonetheless the large Meta-analysis Global Group in Chronic Heart Failure (MAGGIC), including data from clinical trials, has reported a considerably lower mortality rate in HFpEF compared with HFrEF patients  [
      • Pocock S.J.
      • Ariti C.A.
      • McMurray J.J.V.
      • Maggioni A.
      • Køber L.
      • Squire I.B.
      • et al.
      Predicting survival in heart failure: A risk score based on 39 372 patients from 30 studies.
      ].

      1.2 Does HFpEF represent true HF or just a collection of comorbidities? Pathophysiological understanding from translational studies

      HFpEF often occurs in older female patients, suffering with a broad spectrum of comorbidities, ranging from hypertension and diabetes mellitus to pulmonary disease and cancer. All these conditions are characterized by low-grade chronic inflammation, endothelial dysfunction, cardiac fibrosis and increased ventricular stiffness, which constitute key pathological features of HFpEF [
      • Simmonds S.J.
      • Cuijpers I.
      • Heymans S.
      • Jones E.A.V.
      Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding.
      ] (Fig. 1). Extra-cardiac metabolic and systemic inflammatory risk factors exert a pivotal role in the “systemic microvascular paradigm” proposed for HFpEF development [
      • Paulus W.J.
      • Tschöpe C.
      A novel paradigm for heart failure with preserved ejection fraction: Comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.
      ]: chronic conditions produce detrimental low-grade systemic inflammation, with enhanced expression of adhesion molecules on microvascular cells, that in turn determines different degrees of systemic and cardiac inflammation. Indeed, high levels of circulating interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-), and circulating acute inflammatory C-reactive protein (CRP) were detected in patients suffering from HFpEF [
      • Kalogeropoulos A.
      • Georgiopoulou V.
      • Psaty B.M.
      • Rodondi N.
      • Smith A.L.
      • Harrison D.G.
      • et al.
      Inflammatory Markers and Incident Heart Failure Risk in Older Adults. The Health ABC (Health, Aging, and Body Composition) Study.
      ]. Of note, the number of concomitant comorbidities was proportional to CRP levels [
      • DuBrock H.M.
      • AbouEzzeddine O.F.
      • Redfield M.M.
      High-sensitivity C-reactive protein in heart failure with preserved ejection fraction.
      ]. Contrarywise, the “sterile inflammation” model, typical of HFrEF, occurs in response to cardiac remodeling due to cardiomyocyte necrosis following ischemia [
      • Simmonds S.J.
      • Cuijpers I.
      • Heymans S.
      • Jones E.A.V.
      Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding.
      ].
      Microvascular endothelial dysfunction represents an early marker of HFpEF, whereas it constitutes a late event in HFrEF [
      • Paulus W.J.
      • Tschöpe C.
      A novel paradigm for heart failure with preserved ejection fraction: Comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.
      ]. Indeed, the low-grade systemic inflammation, induced by concomitant comorbidities, alters nitric oxide (NO) endothelial production, and enhances eNOS uncoupling. Accordingly, signaling abnormalities leading to oxidative stress, such as reduced activity of protein kinase G (PKG) and diminished concentrations of cyclic guanosine monophospate (cGMP), have been detected in myocardial biopsies from human HFpEF. These alterations are responsible for reduced vasodilator capacity of the coronary endothelium, increased cardiomyocyte hypertrophy and myocyte passive stiffness [
      • Franssen C.
      • Chen S.
      • Unger A.
      • Korkmaz H.I.
      • De Keulenaer G.W.
      • Tschöpe C.
      • et al.
      Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction.
      ,
      • Van Heerebeek L.
      • Hamdani N.
      • Falcão-Pires I.
      • Leite-Moreira A.F.
      • Begieneman M.P.V.
      • Bronzwaer J.G.F.
      • et al.
      Low myocardial protein kinase G activity in heart failure with preserved ejection fraction.
      ].
      Importantly, endothelial dysfunction has been associated with reduced estrogen production, thus suggesting a potential explanation to the higher prevalence of HFpEF among post-menopausal women. Indeed, estrogens participate in the regulation of vascular tone through increased prostaglandins and NO production, enhanced eNOS expression, and reduction of sympathetic activity [
      • Simmonds S.J.
      • Cuijpers I.
      • Heymans S.
      • Jones E.A.V.
      Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding.
      ]. Furthermore, although the exact role of estrogens in HFpEF development needs to be further clarified, estradiol administration has been demonstrated to significantly contrast diastolic dysfunction in postmenopausal women with arterial hypertension [
      • Alecrin I.N.
      • Aldrighi J.M.
      • Caldas M.A.
      • Gebara O.C.E.
      • Lopes N.H.M.
      • Ramires J.A.F.
      Acute and chronic effects of oestradiol on left ventricular diastolic function in hypertensive postmenopausal women with left ventricular diastolic dysfunction.
      ] and to prevent HFpEF development in preclinical studies [
      • Dhot J.
      • Prat V.
      • Stevant D.
      • Ferron M.
      • Persello A.
      • Aillerie V.
      • et al.
      Phytoestrogen: Protective effect in HFpEF through ageing?.
      ].
      HFrEF patients mainly show ventricular eccentric remodeling, determined by cardiomyocytes damage and loss, with minimal alteration in wall thickness; contrarywise, people suffering from HFpEF generally show concentric cardiomyocyte hypertrophy, with increased ventricle wall thickness. These differences can be explained by specific cardiomyocyte peculiarities emerged from the comparison of cardiac biopsies of the two HF subgroups, with HFpEF phenotype showing higher myofibrillar density, thicker cardiomyocytes and increased cardiomyocyte passive stiffness [
      • Van Heerebeek L.
      • Borbély A.
      • Niessen H.W.M.
      • Bronzwaer J.G.F.
      • Van Der Velden J.
      • Stienen G.J.M.
      • et al.
      Myocardial structure and function differ in systolic and diastolic heart failure.
      ].
      Although cardiomyocyte cell death constitutes a typical HFrEF feature, apoptosis and autophagy inhibition resulted in improvement of diastolic function in a murine model of HFpEF, allowing to speculate on a potential role exerted by these two processes also in cardiomyocyte hypertrophy and stiffness during HFpEF [
      • Chaanine A.H.
      • Kohlbrenner E.
      • Gamb S.I.
      • Guenzel A.J.
      • Klaus K.
      • Fayyaz A.U.
      • et al.
      FOXO3A regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress.
      ]. However, further evidence is needed to better clarify the cellular mechanisms underlying HFpEF.
      Increased cardiac interstitial fibrosis represents another peculiar feature of HFpEF which develops in response to myofibroblast activation due to oxidative stress, triggered by diabetes mellitus, aging, hypertension and pressure overload [
      • Simmonds S.J.
      • Cuijpers I.
      • Heymans S.
      • Jones E.A.V.
      Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding.
      ]. In HFpEF, cardiac stiffness also results from excessive deposition of collagen and reduced quantity of more flexible collagen type III [
      • Echegaray K.
      • Andreu I.
      • Lazkano A.
      • Villanueva I.
      • Sáenz A.
      • Elizalde M.R.
      • et al.
      Role of Myocardial Collagen in Severe Aortic Stenosis With Preserved Ejection Fraction and Symptoms of Heart Failure.
      ]. In this context, a crucial role is exerted by the pro-fibrotic TGFβ1 signaling whose activation induces fibroblast trans-differentiation in myofibroblast and extracellular matrix synthesis and deposition, as also confirmed by the higher serum levels of TGFβ1 detected in HFpEF patients [
      • Bielecka-Dabrowa A.
      • Sakowicz A.
      • Misztal M.
      • von Haehling S.
      • Ahmed A.
      • Pietrucha T.
      • et al.
      Differences in biochemical and genetic biomarkers in patients with heart failure of various etiologies.
      ]. Furthermore, HFpEF patients show higher levels of chemokines, such as monocyte chemoattractant protein 1 (MCP-1) responsible for the recruitment of pro-fibrotic circulating progenitors [
      • Haudek S.B.
      • Cheng J.
      • Du J.
      • Wang Y.
      • Hermosillo-Rodriguez J.
      • Trial J.A.
      • et al.
      Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy.
      ]. Taken together, these processes determine immune cells infiltration close to vasculature, with perivascular fibrosis.
      Moreover, together with fibrillar collagen, alteration in titin, a bidirectional giant spring, is also associated with diastolic stiffness. In animal HFpEF models, presenting arterial hypertension, obesity and diabetes mellitus, the switch from the flexible N2BA titin isoform to the less elastic N2B one has been observed and associated with an increased cardiomyocyte passive stiffness [
      • Simmonds S.J.
      • Cuijpers I.
      • Heymans S.
      • Jones E.A.V.
      Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding.
      ].
      Furthermore, with regard to altered relaxation in HFpEF, a key role is exerted by reduced intracellular calcium removal. Indeed, in isolated myocardium of HFpEF patients, incomplete relaxation and increased diastolic tension have been found in association with elevated resting sarcomere calcium levels, which are not dependent on sodium gradient [
      • Runte K.E.
      • Bell S.P.
      • Selby D.E.
      • Häußler T.N.
      • Ashikaga T.
      • Lewinter M.M.
      • et al.
      Relaxation and the Role of Calcium in Isolated Contracting Myocardium from Patients with Hypertensive Heart Disease and Heart Failure with Preserved Ejection Fraction.
      ].
      Finally, neurohormonal activation represents a key event in HFrEF pathophysiology with tremendous implications in term of morbidity and mortality, even regardless of comorbidities [
      • Bencivenga L.
      • Komici K.
      • Femminella G.D.
      • Paolillo S.
      • Gargiulo P.
      • Formisano R.
      • et al.
      Impact of the number of comorbidities on cardiac sympathetic derangement in patients with reduced ejection fraction heart failure.
      ]. Although neurohormonal hyperactivity has been reported in patients with HFpEF [
      • Badrov M.B.
      • Mak S.
      • Floras J.S.
      Cardiovascular Autonomic Disturbances in Heart Failure With Preserved Ejection Fraction.
      ], it appears to be less prevalent and of lower extent than in HFrEF [
      • Vergaro G.
      • Aimo A.
      • Prontera C.
      • Ghionzoli N.
      • Arzilli C.
      • Zyw L.
      • et al.
      Sympathetic and renin-angiotensin-aldosterone system activation in heart failure with preserved, mid-range and reduced ejection fraction.
      ,
      • Jimenez-Marrero S.
      • Moliner P.
      • Rodríguez-Costoya I.
      • Enjuanes C.
      • Alcoberro L.
      • Yun S.
      • et al.
      Sympathetic activation and outcomes in chronic heart failure: Does the neurohormonal hypothesis apply to mid-range and preserved ejection fraction patients?.
      ]. Of interest, cardiac beta-adrenergic receptor hyperactivation induces an increase in G protein-coupled Receptor Kinase-2 (GRK2) expression/activity, which, in turn, triggers receptor desensitization/downregulation. In a recent study, our group has reported that GRK2 levels in cardiac biopsies of HFpEF patients are significantly lower compared to HFrEF hearts, suggesting lower sympathetic activation and beta-adrenergic receptor dysfunction in HFpEF compared to HFrEF [
      • D'Assante R.
      • Arcopinto M.
      • Rengo G.
      • Salzano A.
      • Walser M.
      • Gambino G.
      • et al.
      Myocardial expression of somatotropic axis, adrenergic signalling, and calcium handling genes in heart failure with preserved ejection fraction and heart failure with reduced ejection fraction.
      ]. Furthermore, pharmacological inhibition of neurohormonal activity in HFpEF failed to show any impact on survival and the observed hyperactivation may be related to comorbidities such as diabetes mellitus, obesity, and sleep apnea. Thus, the relevance and pathophysiological implications of sympathetic and renin-angiotensin-aldosterone hyperactivation in HFpEF needs further clarification in future studies.
      Another relevant aspect regarding the understanding of HFpEF concerns the presence of concomitant multiple anabolic deficits. This assumption stems from the observation, already known from two decades, that the presence of isolated and/or concomitant alterations of the main anabolic hormonal axes has a relevant impact on the natural history, morbidity and mortality of HFrEF [
      • Iacoviello M.
      • Parisi G.
      • Gioia M.I.
      • Grande D.
      • Rizzo C.
      • Guida P.
      • et al.
      Thyroid Disorders and Prognosis in Chronic Heart Failure: A Long-Term Follow-Up Study.
      ,
      • Maggio M.
      • Cattabiani C.
      • Lauretani F.
      • Ferrucci L.
      • Luci M.
      • Valenti G.
      • et al.
      The concept of multiple hormonal dysregulation.
      ,
      • Arcopinto M.
      • Salzano A.
      • Giallauria F.
      • Bossone E.
      • Isgaard J.
      • Marra A.M.
      • et al.
      Growth hormone deficiency is associated with worse cardiac function, physical performance, and outcome in chronic heart failure: Insights from the T.O.S.CA. GHD study.
      ,
      • Cittadini A.
      • Salzano A.
      • Iacoviello M.
      • Triggiani V.
      • Rengo G.
      • Cacciatore F.
      • et al.
      Multiple hormonal and metabolic deficiency syndrome predicts outcome in heart failure: the T.O.S.CA. Registry.
      ]. According to a report from Salzano and collaborators, more than half of HFpEF patients have at least 1 hormonal deficiency, mainly growth hormone/insulin-like growth factor 1 and testosterone deficiency. However, the number of hormonal deficiencies was significatively lower in HFpEF patients compared to HFrEF ones [
      • Salzano A.
      • Marra A.M.
      • Ferrara F.
      • Arcopinto M.
      • Bobbio E.
      • Valente P.
      • et al.
      Multiple hormone deficiency syndrome in heart failure with preserved ejection fraction.
      ]. A subsequent study performed by the same group attempted to clarify possible differences between the two conditions [
      • Arcopinto M.
      • Salzano A.
      • Giallauria F.
      • Bossone E.
      • Isgaard J.
      • Marra A.M.
      • et al.
      Growth hormone deficiency is associated with worse cardiac function, physical performance, and outcome in chronic heart failure: Insights from the T.O.S.CA. GHD study.
      ]. Myocardial biopsies were obtained from patients undergoing elective cardiac surgery. After total RNA extraction it emerged that patients with HFrEF showed different pathways of somatotropic axis regulation with lower GH receptor expression and increased IGF-1 receptor expression, in the absence of differences in IGF-1 RNA between the two forms. In addition, significant differences were found in genes involved in adrenergic signaling and calcium handling. These led authors to speculate that a different mileau of genes involved is likely to explain the different response to drugs recorded in the majority of trials enrolling HFpEF patients.

      1.3 Are distinct cardiovascular abnormalities discernable in HFpEF?

      A consistent body of evidence supports the possible existence of a specific pattern of cardiovascular abnormalities in HFpEF (Fig. 2). A larger LV mass, greater systolic and diastolic dysfunction, more significant LA enlargement, and increased arterial stiffness have been found in 386 patients with HFpEF compared with age and sex-matched controls and with hypertensive group. These differences persist even after accounting for age, sex, body size, and comorbidities, patients with HFpEF [
      • Mohammed S.F.
      • Borlaug B.A.
      • Roger V.L.
      • Mirzoyev S.A.
      • Rodeheffer R.J.
      • Chirinos J.A.
      • et al.
      Comorbidity and ventricular and vascular structure and function in heart failure with preserved ejection fraction a community-based study.
      ]. In a landmark study of Morris and coworkers [
      • Morris D.A.
      • Boldt L.H.
      • Eichstädt H.
      • Özcelik C.
      • Haverkamp W.
      Myocardial systolic and diastolic performance derived by 2-dimensional speckle tracking echocardiography in heart failure with normal left ventricular ejection fraction.
      ] a more impaired LV myocardial systolic and diastolic performance than asymptomatic patients with LV diastolic dysfunction (LVDD) and healthy subjects have been found. These abnormalities were in turn associated with elevated LV filling pressures (mitral E/e' average septal-lateral ratio ≥13), low cardiac output (CO ≤2.2 L/min per m2 or ≤5 L/min), and low stroke volume (SV ≤35 mL/m2) [
      • Morris D.A.
      • Boldt L.H.
      • Eichstädt H.
      • Özcelik C.
      • Haverkamp W.
      Myocardial systolic and diastolic performance derived by 2-dimensional speckle tracking echocardiography in heart failure with normal left ventricular ejection fraction.
      ]. Besides LV abnormalities, also right ventricle (RV) plays a pivotal role in HFpEF in terms of risk stratification, regardless of the technique endowed to unmask its dysfunction [
      • Marra A.M.
      • Sherman A.E.
      • Salzano A.
      • Guazzi M.
      • Saggar R.
      • Squire I.B.
      • et al.
      Right Heart-Pulmonary Circulation Unit Involvement in Left-sided Heart Failure: Diagnostic, Prognostic and Therapeutic Implications. From the Forgotten Chamber to the Chamber of Secrets.
      ]. In addition, RV dysfunction progression over time is also strongly associated with poorer outcomes. According to a recent study elegantly performed by Obokata M et al. [
      • Obokata M.
      • Reddy Y.N.V.
      • Melenovsky V.
      • Pislaru S.
      • Borlaug B.A.
      Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction.
      ] the progression of RV enlargement and systolic impairment in HFpEF was found to be associated with 35% increase of all-cause mortality and 85% rise in CV mortality. Notably changes in structure and function in right ventricle greatly exceeded those observed in the LV over time [
      • Obokata M.
      • Reddy Y.N.V.
      • Melenovsky V.
      • Pislaru S.
      • Borlaug B.A.
      Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction.
      ].
      Fig. 2
      Fig. 2Specific cardiovascular abnormalities in HFpEF.

      1.4 The HFpEF galaxy: phenotyping and treating comorbidities in HFpEF

      One of the major unsolved issues regarding HFpEF is that the term has been generically used to define all cases of HF without a rough and easily recognizable systolic dysfunction. This phrasing led over the years to label as HFpEF several different phenotypes showing vast heterogeneity in clinical presentation, phenotyping, and especially in natural history [
      • Sorimachi H.
      • Omote K.
      • Borlaug B.A.
      Clinical Phenogroups in Heart Failure with Preserved Ejection Fraction.
      ]. The need for thoroughly categorize patients with HFpEF stems from the failure of the vast majority of treatments used in HFrEF to equally impact on the natural history of HFpEF [
      • Francis G.S.
      • Cogswell R.
      • Thenappan T.
      The heterogeneity of heart failure: Will enhanced phenotyping be necessary for future clinical trial success?.
      ]. An Interesting attempt has been performed in a post-hoc analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) trial. In this study a latent-class analysis was used to cluster different HFpEF subgroups according to clinical presentation, serum levels of multiple biomarkers, left ventricular architecture and function, arterial stiffness and clinical outcomes [
      • Cohen J.B.
      • Schrauben S.J.
      • Zhao L.
      • Basso M.D.
      • Cvijic M.E.
      • Li Z.
      • et al.
      Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone.
      ]. According to this report, three main phenogroups were identified: 1) mildly symptomatic patients with evidence of LV hypertrophy and arterial stiffness; 2) elderly with atrial fibrillation, enlarged left atrium and increased serum level of biomarkers of innate immunity and vascular calcification; 3) severely clinical impaired patients with obesity, renal and liver failure and increased levels of biomarkers of inflammatory activation [
      • Cohen J.B.
      • Schrauben S.J.
      • Zhao L.
      • Basso M.D.
      • Cvijic M.E.
      • Li Z.
      • et al.
      Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone.
      ]. Phenogroups 2 and 3 showed similar mortality and both reduced survival, when compared to phenogroup 1. Interestingly, phenogroup 3 was associated with a more pronounced response to spironolactone in reducing the primary end-point (HR: 0.75; 95% CI: 0.59 to 0.95; p for interaction = 0.016). Narrowing cardiac abnormalities to a single comorbidity, an interesting study has been published by Obokata and colleagues, focusing on the role of obesity in HFpEF. In this report, obese HFpEF patients showed increased epicardial fat, left ventricular mass and worse right heart dysfunction with impaired lung hemodynamics [
      • Obokata M.
      • Reddy Y.N.V.
      • Pislaru S.V.
      • Melenovsky V.
      • Borlaug B.A.
      Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure with Preserved Ejection Fraction.
      ]. These finding led to the speculation that HFpEF with concomitant obesity may display a different phenotype, and these is likely to deserve a specific treatment.
      On the other hand, an analysis perfomed on 31,344 patients enrolled in the Swedish Heart Failure Registry (SwedeHF) sought to report the prevalence and prognostic contribution of individual and aggregates non-cardiac comorbidities in HFpEF [
      • Ergatoudes C.
      • Schaufelberger M.
      • Andersson B.
      • Pivodic A.
      • Dahlström U.
      • Fu M.
      Non-cardiac comorbidities and mortality in patients with heart failure with reduced vs. preserved ejection fraction: a study using the Swedish Heart Failure Registry.
      ]. Stroke, anemia, gout and cancer had the strongest impact on mortality on HFpEF. An interesting finding of this study is that no variation of mortality for any of the comorbidities was reported during the past decade despite treatment for comorbidities improved. This finding might lead to speculate on the possible prognostic role of the net effect of treating concomitant conditions in HFpEF on morbidity and mortality. For this reason, the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) study was designed [
      • Fonarow G.C.
      • Abraham W.T.
      • Albert N.M.
      • Gattis W.A.
      • Gheorghiade M.
      • Greenberg B.
      • et al.
      Organized program to initiate lifesaving treatment in hospitalized patients with heart failure (OPTIMIZE-HF): Rationale and design.
      ]. This study is aimed in testing whether a model for screening and optimally treating the most frequent cardiovascular, metabolic, respiratory, and renal comorbidities exerts a positive effect on hard clinical outcomes. The results of this study have still to be published and will gather important insights into the interplay between comorbidities and HFpEF.
      In such a complex scenario, the case of transthyretin-related cardiac amyloidosis (ATTR) is paradigmatic. Underdiagnosed until the last decade, ATTR is increasingly being recognized as one of the main contributors to the spread of HF, especially among elderly, accounting for a significant proportion (up to 13%) of HFpEF cases in the wild type ATTR [
      • González-López E.
      • Gallego-Delgado M.
      • Guzzo-Merello G.
      • De Haro-Del Moral F.J.
      • Cobo-Marcos M.
      • Robles C.
      • et al.
      Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction.
      ]. Importantly, it represents the first disease, within the spectrum of conditions leading to HFpEF, with an efficacious etiological treatment [
      • Maurer M.S.
      • Schwartz J.H.
      • Gundapaneni B.
      • Elliott P.M.
      • Merlini G.
      • Waddington-Cruz M.
      • et al.
      Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.
      ]. Since specific features in terms of hemodynamic and reduced tolerance to HF pharmacological measures, it has been even supposed that the presence a subset of enrolled patients with undiagnosed cardiac amyloidosis might have contributed to the failure of HFpEF trials so far [
      • Oghina S.
      • Bougouin W.
      • Bézard M.
      • Kharoubi M.
      • Komajda M.
      • Cohen-Solal A.
      • et al.
      The Impact of Patients With Cardiac Amyloidosis in HFpEF Trials.
      ].
      Following these premises, the need for further research is evident with the aim of an even more accurate phenotyping of HFpEF, in order to allow a tailored type-specific diagnostic and therapeutic approach.

      1.5 Randomized clinical trials in HFpEF: requiem for a funeral?

      As already mentioned, randomized clinical trials in HFpEF represented a frustrating losing streak so far, up to the recent publication of the data from the EMPEREOR-preserved trial.
      Table 1 summarizes the main results of the principal and larger randomized placebo-controlled multicenter trials in this condition. The most interesting finding is the non-negligible proportion of deaths due to non-cardiac causes in almost all study populations, ranging from 6 to 7% (Table 1). This was also confirmed by some registry data showing that non-cardiovascular mortality (specifically from cancer, chronic kidney disease, sepsis, and respiratory disease) represents by far the most preponderant in HFpEF (62%) whereas it is of lesser significance in HFrEF (35%) [
      • Vergaro G.
      • Ghionzoli N.
      • Innocenti L.
      • Taddei C.
      • Giannoni A.
      • Valleggi A.
      • et al.
      Noncardiac Versus Cardiac Mortality in Heart Failure With Preserved, Midrange, and Reduced Ejection Fraction.
      ]. This supports the view that the main drivers of disease progression are precisely non-cardiovascular comorbidities. In fact, in the previous studies were used drugs active on the cardiovascular system while the first positive trial is the recently published EMPEREOR-preserved, in which empagliflozin, a sodium glucose co-transporter 2 inhibitor, a molecule originally used in the treatment of type 2 diabetes mellitus, has been employed. However, a clarification is necessary. First of all, HFpEF trials differ remarkably in terms of cut-off of ejection fraction used, follow-up and inclusion/exclusion criteria. This could have led to the differences in results between these studies. Moreover, Although the primary endpoint (composite of cardiovascular death and HF hospitalization), was achieved in the EMPEROR-preserved (HR, 0.79; 95% CI, 0.69 to 0.90; P<0.001), it was driven primarily by the reduction in the number of hospitalizations in the empagliflozin-treated group (HR 0.73; 95% CI, 0.61 to 0.88; P<0.001) without a significant reduction in all-cause mortality (HR 0.92, 95% CI 0.77 to 1.10, p > 0.05). This implies that although this trial represents a turning point in the history of this disease, empagliflozin is only a curb on disease progression without constituting a definitive cure.
      Table 1LVEF: Left Ventricular Ejection Fraction; HF: Heart Failure, nr: not reported; NP: natriuretic peptides; LV: left ventricular; LA: left atrial.
      AcronymYear of publicationInterventionSample sizeFemale (%)HFpEF definitionPrimary OutcomeOccurrence of the primary outcomenon-CV mortality
      CHARM-Preserved
      • Yusuf S.
      • Pfeffer M.A.
      • Swedberg K.
      • Granger C.B.
      • Held P.
      • McMurray J.J.V.
      • et al.
      Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.
      2003Candersartan (4 mg up to 32 mg daily) vs placebo302340.1LVEF ≧ 40% and Hospital admission for HFComposite of cardiovascular death or hospital admission for HFCandesartan: 22% Placebo: 24%nr
      PEP-CHF
      • Cleland J.G.F.
      • Tendera M.
      • Adamus J.
      • Freemantle N.
      • Polonski L.
      • Taylor J.
      • et al.
      The perindopril in elderly people with chronic heart failure (PEP-CHF) study.
      2006Perindopril (4 mg daily) vs Placebo85054.9LVEF ≧ 40% treated with diuretics for a diastolic HFComposite of all-cause mortality and unplanned heart failure related hospi- talizationPerindopril: 23.6% Placebo: 25.1%Perindopril: 1,65% Placebo:0,5%
      DIG
      • Ahmed A.
      • Rich M.W.
      • Fleg J.L.
      • Zile M.R.
      • Young J.B.
      • Kitzman D.W.
      • et al.
      Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial.
      2006Digoxin (0.125 mg up to 0.50 mg daily) vs Placebo98841.2LVEF ≧ 45% plus Sinus RhythmComposite of HF mortality or HF hospitalizationDigoxin: 20.7% Placebo: 24%Digoxin: 6,9% Placebo: 7,1
      I-PRESERVE
      • Massie B.M.
      • Carson P.E.
      • McMurray J.J.
      • Komajda M.
      • McKelvie R.
      • Zile M.R.
      • et al.
      Irbesartan in patients with heart failure and preserved ejection fraction.
      2008Irbesartan (75 mg up to 300 mg) vs Placebo412861.1LVEF ≧ 45% plus history of HF in the previous 6-monthsComposite of death from any cause or hospitalization for a protocol-specified cardiovascular causeIrbesartan: 35.9% Placebo: 37.0%Irbesartan: 6.5% Placebo: 6.5%
      TOPCAT
      • Bertram P.
      • Pfeffer M.A.
      • Assmann S.F.
      • Boineau R.
      • Anand I.S.
      • Claggett B.
      • et al.
      Spironolactone for heart failure with preserved ejection fraction.
      (24,716,680)
      2014Spironolactone (15 mg up to 45 mg daily) vs placebo344551.5LVEF ≧ 45% plus history of HF in the previous 12-months and/or increased NPComposite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure.spironolactone:18.6% placebo: 20.4%Spirolonolactone: 92 (5.3%) Placebo: 98 (5.7%)
      PARAGON HF
      • Solomon S.D.
      • McMurray J.J.V.
      • Anand I.S.
      • Ge J.
      • Lam C.S.P.
      • Maggioni A.P.
      • et al.
      Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.
      2019sacubitril/valsartan (target dose, 97/ 103 mg twice daily) vs valsartan (target dose, 160 mg twice daily).482251.4LVEF ≧ 45% plus increased NPComposite of total hospitalizations for heart fail- ure and death from cardiovascular causes.Sacubitril/Valsartan: 37.2% Valsartan: 42.2%Sacubitril/Valsartan: 5.7% Valsartan: 5.7%
      EMPEREOR-Preserved
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Ferreira J.P.
      • Bocchi E.
      • Böhm M.
      • et al.
      Empagliflozin in Heart Failure with a Preserved Ejection Fraction.
      2021Empagliflozin (10 mg once daily) vs placebo598844,6LVEF ≧ 40% + increased NP + evidence of cardiac structural abnormality (increased LV mass, increased LA volume)Composite of cardiovascular death or hospital admission for HFEmpagliflozin: 13.8% Placebo: 17.1% (HR:0.79, 95% CI: 0.69–0.90, p< 0.001)Empagliflozin: 6.7% Placebo: 6.1%
      LVEF: Left Ventricular Ejection Fraction; HF: Heart Failure, nr: not reported; NP: natriuretic peptides; LV: left ventricular; LA: left atrial.

      2. Conclusion

      In conclusion HFpEF and HFrEF show different features in terms of cardiac abnormalities and concomitant comorbidities. For this reason, it is worth to consider them as two separate syndromes, characterized by increasing prevalence and high mortality. Both epidemiological and mechanistic studies support the concept that HFpEF represents true HF although aggravated by a collection of comorbidities. There is urgent need for improveing its phenotyping due to the high degree of disease heterogeneity within HFpEF, that lead to the failure of randomized clinical trials in demonstrating a remarkable impact of drugs in improving its morbidity and mortality. At this regard, the recently published data from the EMPEROR-Preserved trial demonstrated a remarkable impact of the Sodium-Glucose cotransporter 2 Empaglifozin in reducing a combined endpoint of cardiovascular death or hospitalization due to HFpEF decompensation. Interestingly, this trial showed that Empaglifozin was able to reduce the occurrence of the primary endpoint regardless of the presence of Type 2 Diabetes. This study represents the first evidence of beneficial treatment of a drug in HFpEF and may lead to the development of a new therapeutic approach in this disease.

      Acknowledgements

      Dr. Leonardo Bencivenga has been supported by the research grant provided by the CardioPaTh PhD program, the research grant provided by the FDIME and the STAR PLUS
      Research Grant provided by University of Naples Federico II.

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